The endoplasmic reticulum (ER) is a cellular compartment responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. Myriad pathological and physiological factors perturb ER function and cause dysregulation of ER homeostasis, leading to ER stress. Cells cope with ER stress by activating the ER stress signaling pathways, also known as the unfolded protein response (UPR). This activation results in restoration of ER homeostasis and protects cells from ER stress. Increasing evidence indicates that ER-stress-mediated -cell death has a role in the pathogenesis of type 1 and type 2 diabetes, as well as the death of isolated donor cells for transplantation. Our goal is to understand the role of ER stress in cell death and development of diabetes. Our specific aims for this project are as follows. Aim 1. to investigate misregulation of the UPR in Wolfram syndrome. Aim 2. to determine the role of AATF in the survival of human and mouse primary islets in vivo. Aim 3. to study the role of pro-apoptotic pathway regulated by TXNIP in cells. PUBLIC HEALTH RELEVANCE: Diabetes is a group of disorders defined by hyperglycemia caused by an absolute deficiency (type 1 diabetes) or a relative deficiency of insulin (type 2 diabetes). Insulin, a hormone secreted from pancreatic cells, functions in lowering blood glucose. Increasing evidence indicates that cellular stress caused by the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER), termed ER stress, is directly related to cell dysfunction and death during the progression of type 1 and type 2 diabetes, and Wolfram syndrome, a genetic form of diabetes. To counteract ER stress, cells activate cellular signaling pathways termed the unfolded protein response (UPR). Depending on the nature of the stress condition, the UPR either protects cells or promotes their death. The mechanisms of this switch are not well understood but involve the balance between adaptive and apoptotic factors regulated by the UPR. In this grant application, we study this UPR balancing act between life and death and the mechanisms involved. This area is especially important in understanding the mechanisms of cell death during the progression of diabetes. Diabetes is one of the top ten causes of death in the U.S. affecting 23.6 million people with a total economic cost of $174 billion in 2007. We have identified important survival and death components of the UPR. To study the regulation and function of these molecules in the context of ER stress and cells may reveal new information on how chronic ER stress induces cell death and perhaps novel targets for diabetes prevention or treatment.